tbuckley/cabot-search huggingface dataset:
Efficient delivery of Temozolomide using ultrasmall large-pore silica nanoparticles for glioblastoma
Authors: Taskeen Iqbal Janjua, Yuxue Cao, Aria Ahmed-Cox, Aun Raza, Md Moniruzzaman, Dewan Taslima Akhter, Nicholas L. Fletcher, Maria Kavallaris, Kristofer J. Thurecht, Amirali Popat
Journal: Journal of Controlled Release (2023)

The prognosis of brain cancers such as glioblastoma remains poor despite numerous advancements in the field of neuro-oncology. The presence of the blood brain barrier (BBB) along with the highly invasive and aggressive nature of glioblastoma presents a difficult challenge for developing effective therapies. Temozolomide (TMZ) is a first line agent used in the clinic for glioblastoma and it has been useful in increasing patient survival rates. However, TMZ suffers from issues related to its pharmacokinetics, such as a short plasma half-life (2 h), is subjected to P-gp efflux, and has limited extravasation from blood to brain (∼20%). It has been postulated that reducing its efflux and increasing glioblastoma tissue exposure to TMZ could prove useful in treating glioblastoma and preventing tumour recurrence. Herein, ultra-small, large pore silica nanoparticles (USLP) have been loaded with TMZ, surface PEGlyated to reduce efflux and decorated with the cascade targeting protein lactoferrin for efficient uptake across the BBB and into glioblastoma. Our results demonstrate that USLP improves permeability of BBB in vitro as evidenced using a transwell model which mimics endothelial tight junctions with permeation being enhanced using PEGylated particles. Data from TMZ loaded USLP in vitro transwell BBB model also suggests that the USLP formulations can significantly reduce the efflux ratio of TMZ. In vitro apoptosis studies on glioblastoma cell lines U87 and GL261 were conducted which showed an improvement in TMZ induced glioblastoma apoptosis with USLP formulations compared to pure TMZ. Finally, a proof-of-concept preclinical mouse study demonstrated that when given intravenously at 50 mg/kg, USLP particles showed accumulation in the brain within a few hours without any obvious pathophysiological changes in vital organs as assessed via histology. Overall, the data suggests our innovative delivery system is efficient in extravasation from blood and permeating the BBB and has potential to improve efficacy of TMZ in glioblastoma therapy.
<i>JAK2</i> unmutated erythrocytosis: 2023 Update on diagnosis and management
Authors: Naseema Gangat, Natasha Szuber, Ayalew Tefferi
Journal: American Journal of Hematology (2023)

JAK2 unmutated or non-polycythemia vera (PV) erythrocytosis encompasses a heterogenous spectrum of hereditary and acquired entities.Foremost in the evaluation of erythrocytosis is the exclusion of PV through JAK2 (inclusive of exons 12-15) mutation screening. Initial assessment should also include gathering of previous records on hematocrit (Hct) and hemoglobin (Hgb) levels, in order to streamline the diagnostic process by first distinguishing longstanding from acquired erythrocytosis; subsequent subcategorization is facilitated by serum erythropoietin (Epo) measurement, germline mutation screening, and review of historical data, including comorbid conditions and medication list. Hereditary erythrocytosis constitutes the main culprit in the context of longstanding erythrocytosis, especially when associated with a positive family history. In this regard, a subnormal serum Epo level suggests EPO receptor mutation. Otherwise, considerations include those associated with decreased (high oxygen affinity Hgb variants, 2,3-bisphosphoglycerate deficiency, PIEZO1 mutations, methemoglobinemia) or normal oxygen tension at 50% Hgb saturation (P50). The latter include germline oxygen sensing pathway (HIF2A-PHD2-VHL) and other rare mutations. Acquired erythrocytosis commonly results from central (e.g., cardiopulmonary disease, high-altitude habitat) or peripheral (e.g., renal artery stenosis) hypoxia. Other noteworthy conditions associated with acquired erythrocytosis include Epo-producing tumors (e.g., renal cell carcinoma, cerebral hemangioblastoma) and drugs (e.g., testosterone, erythropoiesis stimulating agents, sodium-glucose cotransporter-2 inhibitors). Idiopathic erythrocytosis is an ill-defined terminology that presumes the existence of an increased Hgb/Hct level without an identifiable etiology. Such classification often lacks accounting for normal outliers and is marred by truncated diagnostic evaluation.Current consensus treatment guidelines are not supported by hard evidence and their value is further undermined by limited phenotypic characterization and unfounded concerns for thrombosis. We are of the opinion that cytoreductive therapy and indiscriminate use of phlebotomy should be avoided in the treatment of non-clonal erythrocytosis. However, it is reasonable to consider therapeutic phlebotomy if one were to demonstrate value in symptom control, with frequency determined by symptoms rather than Hct level. In addition, cardiovascular risk optimization and low dose aspirin is often advised.Advances in molecular hematology might result in better characterization of "idiopathic erythrocytosis" and expansion of the repertoire for germline mutations in hereditary erythrocytosis. Prospective controlled studies are needed to clarify potential pathology from JAK2 unmutated erythrocytosis, as well as to document the therapeutic value of phlebotomy.
Haloperidol vs. placebo for the treatment of delirium in ICU patients: a pre-planned, secondary Bayesian analysis of the AID–ICU trial
Authors: Nina C. Andersen-Ranberg, Lone Musaeus Poulsen, Anders Perner, Johanna Hästbacka, Matthew Morgan, Giuseppe Citerio, Marie Oxenbøll Collet, Sven-Olaf Weber, Anne Sofie Andreasen, Morten Bestle, Bülent Uslu, Helle Scharling Pedersen, Louise Gramstrup Nielsen, Kjeld Damgaard, Troels Bek Jensen, Trine Sommer, Nilanjan Dey, Ole Mathiesen, Anders Granholm
Journal: Intensive Care Medicine (2023)
Glycoursodeoxycholic acid regulates bile acids level and alters gut microbiota and glycolipid metabolism to attenuate diabetes
Authors: Bingting Chen, Yu Bai, Fenglian Tong, Junlin Yan, Rui Zhang, Yewei Zhong, Huiwen Tan, Xiaoli Ma
Journal: Gut Microbes (2023)

Accumulating evidence suggests that the bile acid regulates type 2 diabetes mellitus (T2DM) through gut microbiota-host interactions. However, the mechanisms underlying such interactions have been unclear. Here, we found that glycoursodeoxycholic acid (GUDCA) positively regulates gut microbiota by altering bile acid metabolism. GUDCA in mice resulted in higher taurolithocholic acid (TLCA) level and Bacteroides vulgatus abundance. Together, these changes resulted in the activation of the adipose G-protein-coupled bile acid receptor, GPBAR1 (TGR5) and upregulated expression of uncoupling protein UCP-1, resulting in elevation of white adipose tissue thermogenesis. The anti-T2DM effects of GUDCA are linked with the regulation of the bile acid and gut microbiota composition. This study suggests that altering bile acid metabolism, modifying the gut microbiota may be of value for the treatment of T2DM.
<i>Bifidobacterium longum</i> subsp. <i>infantis</i> utilizes human milk urea to recycle nitrogen within the infant gut microbiome
Authors: Xiaomeng You, Asha Rani, Ezgi Özcan, Yang Lyu, David A. Sela
Journal: Gut Microbes (2023)

Human milk guides the structure and function of microbial commensal communities that colonize the nursing infant gut. Indigestible molecules dissolved in human milk establish a microbiome often dominated by bifidobacteria capable of utilizing these substrates. Interestingly, urea accounts for ~15% of total human milk nitrogen, representing a potential reservoir for microbiota that may be salvaged for critical metabolic operations during lactation and neonatal development. Accordingly, B. infantis strains are competent for urea nitrogen utilization, constituting a previously hypothetical phenotype in commensal bacteria hosted by humans. Urease gene expression, downstream nitrogen metabolic pathways, and enzymatic activity are induced during urea utilization to yield elevated ammonia concentrations. Moreover, biosynthetic networks relevant to infant nutrition and development are transcriptionally responsive to urea utilization including branched chain and other essential amino acids. Importantly, isotopically labeled urea nitrogen is broadly distributed throughout the expressed B. infantis proteome. This incisively demonstrates that the previously inaccessible urea nitrogen is incorporated into microbial products available for infant host utilization. In aggregate, B. infantis possesses the requisite phenotypic foundation to participate in human milk urea nitrogen recycling within its infant host and thus may be a key contributor to nitrogen homeostasis early in life.
Retraction Notice to: lncRNA RMST Enhances DNMT3 Expression through Interaction with HuR
Authors: Wan-Xin Peng, Pratirodh Koirala, Wei Zhang, Chao Ni, Zheng Wang, Liu Yang, Yin-Yuan Mo
Journal: Molecular Therapy (2023)

(Molecular Therapy 28, 9–18; January 2020) This article has been retracted at the request of the editors and corresponding author. This correction has been retracted because the article that it relates to has now been retracted at the request of the editors and corresponding author (Yin-Yuan Mo). RETRACTED: IncRNA RMST Enhances DNMT3 Expression through Interaction with HuRPeng et al.Molecular TherapyFebruary 2, 2023In BriefThis article has been retracted: please see Elsevier Policy on Article Withdrawal ( http://www.elsevier.com/locate/withdrawalpolicy ). This article has been retracted at the request of the editors and corresponding author. This correction has been retracted because the article that it relates to has now been retracted at the request of the editors and corresponding author (Yin-Yuan Mo). Full-Text PDF Open Access
Retraction Notice to: lncRNA RMST Enhances DNMT3 Expression through Interaction with HuR
Authors: Wan-Xin Peng, Pratirodh Koirala, Wei Zhang, Chao Ni, Zheng Wang, Liu Yang, Yin-Yuan Mo
Journal: Molecular Therapy (2023)

(Molecular Therapy 28, 9–18; January 2020) This article has been retracted at the request of the editors and the corresponding author (Yin-Yuan Mo). Concerns regarding potentially duplicated western blots in Figures 2I and 3I were raised by readers on PubPeer (https://pubpeer.com/publications/64075911BAD21941D78C27FD3B8DB3#16), and the authors contacted the editorial office with the original blots to issue a correction. Following the correction of the article, the authors provided additional raw data to address further concerns raised by a reader. Given multiple inconsistencies in file labeling and post-acquisition processing, the editors have lost faith in the findings presented in the article. The retraction notice email was undeliverable to the following authors: Chao Ni, Pratirodh Koirala, Wei Zhang, and Wan-Xin Peng. RETRACTED: lncRNA RMST Enhances DNMT3 Expression through Interaction with HuRPeng et al.Molecular TherapyOctober 4, 2019In BriefThis article has been retracted: please see Elsevier Policy on Article Withdrawal ( http://www.elsevier.com/locate/withdrawalpolicy ). Full-Text PDF Open Access
Extrachromosomal Amplification of Human Papillomavirus Episomes Is a Mechanism of Cervical Carcinogenesis
Authors: Nicole M. Rossi, Jieqiong Dai, Yi Xie, Darawalee Wangsa, Kerstin Heselmeyer-Haddad, Hong Lou, Joseph F. Boland, Meredith Yeager, Roberto Orozco, Enrique Alvirez Freites, Lisa Mirabello, Eduardo Gharzouzi, Michael Dean
Journal: Cancer Research (2023)

Abstract HPV16 is the most oncogenic type of human papillomaviruses (HPV). Integration of HPV into the human genome is an important mechanism of carcinogenesis but is absent in at least 30% of HPV16+ tumors. We applied long-read whole-genome sequencing (WGS) to cervical cancer cell lines and tumors to characterize HPV16 carcinogenesis in the absence of integration. Large tandem arrays of full-length and unique truncated viral genomes integrated into multiple chromosomes were identified in two HPV16+ cell lines. The dispersion of characteristic viral variants to multiple integration sites indicates that viral deletions formed as extrachromosomal DNA (a phenomenon we term HPV superspreading). In addition, we identified an HPV16+ cell line with unintegrated (episomal) DNA that has tandem arrays of full-length, truncated, and rearranged HPV16 genomes (multimer episomes). Cytogenetic analysis of this cell line shows intense extrachromosomal HPV staining, including structures resembling double-minute chromosomes. WGS of HPV16+ cervical tumor samples from Latin America revealed that 11 of 20 tumors with only episomal HPV (EP) had intact monomer episomes. The remaining nine EP tumors had multimer and rearranged HPV genomes. The majority (80%) of HPV rearrangements and deletions disrupted the E1 and E2 genes, and EP tumors overexpressed the E6 and E7 viral oncogenes, a similar profile to tumors with HPV integration. Tumors with putative multimer HPV integrations display HPV multimers and concatemers of human and viral sequences. Our data uncovered a novel mechanism for HPV16 to cause cancer without integration through aberrant episomal replication, forming rearranged, mutated, and multimer episomes. Significance: Multimers of the HPV genome are generated in cervical tumors replicating as extrachromosomal episomes, which is associated with deletion and rearrangement of the HPV genome and provides a mechanism for oncogenesis without integration.
International Society of Nephrology first consensus guidance for preclinical animal studies in translational nephrology
Authors: Masaomi Nangaku, A. Richard Kitching, Peter Boor, Alessia Fornoni, Jürgen Floege, P. Toby Coates, Jonathan Himmelfarb, Rachel Lennon, Hans-Joachim Anders, Benjamin D. Humphreys, Fergus J. Caskey, Agnes B. Fogo, Andrea Angeletti, Patricia W. Bedard, Ariela Benigni, Anna Björnson Granqvist, Vera Certikova Chabova, Christos Chatziantoniou, Rolando Claure-Del Granado, Jennifer Cross, Sandrine Damster, Jo-Ann Donner, Frank Eitner, Stanislas Faguer, Antonio Fontanella, Yuri Fujimoto, Joseph Gaut, Leslie Gewin, Pernille B.L. Hansen, John Cijiang He, Jeremy Hughes, Reiko Inagi, Celia Jenkinson, Vivekanand Jha, Mikio Kato, Darren Kelly, Jeffrey Kopp, Ron Korstanje, Romaldas Mačiulaitis, Patrick B. Mark, Hans-Peter Marti, Stephen P. McAdoo, Jeffrey H. Miner, Alberto Ortiz, Samir M. Parikh, Ambra Pozzi, Paola Romagnani, Pierre Ronco, Brad H. Rovin, Julio Saez-Rodriguez, Moin A. Saleem, John A. Sayer, Stuart Shankland, Andrey S. Shaw, Maria José Soler, Yusuke Suzuki, Tomoko Takano, Sydney Tang, Rene Tolba, Ifeoma Ulasi, John Viel, Yoshihisa Yamada, Motoko Yanagita, Takashi Yokoo, Nobuya Yoshida, Darren Yuen, Roy Zent, Aihua Zhang
Journal: Kidney International (2023)

Preclinical tests in animal models are key steps in early drug development. Consequently, the International Society of Nephrology held a consensus meeting that connected experts in the global kidney community in order to provide guidance on optimal management of translational animal studies for the development of new drugs to treat kidney disease, entitled "TRANSFORM; TRAnslational Nephrology Science FOR new Medications." The meeting covered various themes, including the following: (i) selection of disease model; (ii) pharmacokinetics; (iii) interventions in late preclinical models; (iv) choice of animal; (v) statistical power; (vi) organoids and organ-on-a-chip models; and (vii) reporting of results. This guidance is the first to be provided on the optimal conduct of translational animal studies for the development of new drugs to treat kidney disease. These recommendations are designed to accelerate development of new drugs for efficacious treatment of kidney diseases, and to improve the prognosis and quality of life of patients with a variety of kidney diseases.
Interventions Relieving Dyspnea in Intubated Patients Show Responsiveness of the Mechanical Ventilation–Respiratory Distress Observation Scale
Authors: Maxens Decavèle, Côme Bureau, Sébastien Campion, Marie-Cécile Nierat, Isabelle Rivals, Nicolas Wattiez, Morgane Faure, Julien Mayaux, Elise Morawiec, Mathieu Raux, Thomas Similowski, Alexandre Demoule
Journal: American Journal of Respiratory and Critical Care Medicine (2023)

Rationale: Breathing difficulties are highly stressful. In critically ill patients, they are associated with an increased risk of posttraumatic manifestations. Dyspnea, the corresponding symptom, cannot be directly assessed in noncommunicative patients. This difficulty can be circumvented using observation scales such as the mechanical ventilation-respiratory distress observation scale (MV-RDOS). Objective: To investigate the performance and responsiveness of the MV-RDOS to infer dyspnea in noncommunicative intubated patients. Methods: Communicative and noncommunicative patients exhibiting breathing difficulties under mechanical ventilation were prospectively included and assessed using a dyspnea visual analog scale, MV-RDOS, EMG activity of alae nasi and parasternal intercostals, and EEG signatures of respiratory-related cortical activation (preinspiratory potentials). Inspiratory-muscle EMG and preinspiratory cortical activities are surrogates of dyspnea. Assessments were conducted at baseline, after adjustment of ventilator settings, and, in some cases, after morphine administration. Measurements and Main Results: Fifty patients (age, 67 [(interquartile interval [IQR]), 61-76] yr; Simplified Acute Physiology Score II, 52 [IQR, 35-62]) were included, 25 of whom were noncommunicative. Relief occurred in 25 (50%) patients after ventilator adjustments and in 21 additional patients after morphine administration. In noncommunicative patients, MV-RDOS score decreased from 5.5 (IQR, 4.2-6.6) at baseline to 4.2 (IQR, 2.1-4.7; P < 0.001) after ventilator adjustments and 2.5 (IQR, 2.1-4.2; P = 0.024) after morphine administration. MV-RDOS and alae nasi/parasternal EMG activities were positively correlated (ρ = 0.41 and 0.37, respectively). MV-RDOS scores were higher in patients with EEG preinspiratory potentials (4.9 [IQR, 4.2-6.3] vs. 4.0 [IQR, 2.1-4.9]; P = 0.002). Conclusions: The MV-RDOS seems able to detect and monitor respiratory symptoms reasonably well in noncommunicative intubated patients. Clinical trial registered with www.clinicaltrials.gov (NCT02801838).
Race and Ethnicity in Pulmonary Function Test Interpretation: An Official American Thoracic Society Statement
Authors: Nirav R. Bhakta, Christian Bime, David A. Kaminsky, Meredith C. McCormack, Neeta Thakur, Sanja Stanojevic, Aaron D. Baugh, Lundy Braun, Stephanie Lovinsky-Desir, Rosemary Adamson, Jonathan Witonsky, Robert A. Wise, Sean D. Levy, Robert Brown, Erick Forno, Robyn T. Cohen, Meshell Johnson, John Balmes, Yolanda Mageto, Cathryn T. Lee, Refiloe Masekela, Daniel J. Weiner, Charlie G. Irvin, Erik R. Swenson, Margaret Rosenfeld, Richard M. Schwartzstein, Anurag Agrawal, Enid Neptune, Juan P. Wisnivesky, Victor E. Ortega, Peter Burney
Journal: American Journal of Respiratory and Critical Care Medicine (2023)

Current American Thoracic Society (ATS) standards promote the use of race and ethnicity-specific reference equations for pulmonary function test (PFT) interpretation. There is rising concern that the use of race and ethnicity in PFT interpretation contributes to a false view of fixed differences between races and may mask the effects of differential exposures. This use of race and ethnicity may contribute to health disparities by norming differences in pulmonary function. In the United States and globally, race serves as a social construct that is based on appearance and reflects social values, structures, and practices. Classification of people into racial and ethnic groups differs geographically and temporally. These considerations challenge the notion that racial and ethnic categories have biological meaning and question the use of race in PFT interpretation. The ATS convened a diverse group of clinicians and investigators for a workshop in 2021 to evaluate the use of race and ethnicity in PFT interpretation. Review of evidence published since then that challenges current practice and continued discussion concluded with a recommendation to replace race and ethnicity-specific equations with race-neutral average reference equations, which must be accompanied with a broader re-evaluation of how PFTs are used to make clinical, employment, and insurance decisions. There was also a call to engage key stakeholders not represented in this workshop and a statement of caution regarding the uncertain effects and potential harms of this change. Other recommendations include continued research and education to understand the impact of the change, to improve the evidence for the use of PFTs in general, and to identify modifiable risk factors for reduced pulmonary function.
Tail nerve electrical stimulation promoted the efficiency of transplanted spinal cord-like tissue as a neuronal relay to repair the motor function of rats with transected spinal cord injury
Authors: Bi-Qin Lai, Rong-Jie Wu, Wei-Tao Han, Yu-Rong Bai, Jia-Lin Liu, Hai-Yang Yu, Shang-Bin Yang, Lai-Jian Wang, Jia-Le Ren, Ying Ding, Ge Li, Xiang Zeng, Yuan-Huan Ma, Qi Quan, Ling-Yan Xing, Bin Jiang, Ya-Qiong Wang, Ling Zhang, Zheng-Hong Chen, Hong-Bo Zhang, Yuan-Feng Chen, Qiu-Jian Zheng, Yuan-Shan Zeng
Journal: Biomaterials (2023)
Alleviate Periodontitis and Its Comorbidity Hypertension using a Nanoparticle‐Embedded Functional Hydrogel System
Authors: Shuo Xu, Bin Hu, Ting Dong, Bo‐Yan Chen, Xiao‐Jian Xiong, Lin‐Juan Du, Yu‐Lin Li, Yan‐Lin Chen, Guo‐Cai Tian, Xue‐Bing Bai, Ting Liu, Lu‐Jun Zhou, Wu‐Chang Zhang, Yan Liu, Qin‐Feng Ding, Xue‐Qing Zhang, Sheng‐Zhong Duan
Journal: Advanced Healthcare Materials (2023)

Abstract Periodontitis and hypertension often occur as comorbidities, which need to be treated at the same time. To resolve this issue, a controlled‐release composite hydrogel approach is proposed with dual antibacterial and anti‐inflammatory activities as a resolution to achieve the goal of co‐treatment of comorbidities. Specifically, chitosan (CS) with inherent antibacterial properties is cross‐linked with antimicrobial peptide (AMP)‐modified polyethylene glycol (PEG) to form a dual antibacterial hydrogel (CS‐PA). Subsequently, curcumin loaded into biodegradable nanoparticles (CNP) are embedded in the hydrogel exhibiting high encapsulation efficiency and sustained release to achieve long‐term anti‐inflammatory activities. In a mouse model of periodontitis complicated with hypertension, CS‐PA/CNP is applied to gingival sulcus and produced an optimal therapeutic effect on periodontitis and hypertension simultaneously. The therapeutic mechanisms are deeply studied and indicated that CS‐PA/CNP exerted excellent immunoregulatory effects by suppressing the accumulation of lymphocytes and myeloid cells and enhanced the antioxidant capacity and thus the anti‐inflammatory capacity of macrophages through the glutathione metabolism pathway. In conclusion, CS‐PA/CNP has demonstrated its superior therapeutic effects and potential clinical translational value in the co‐treatment of periodontitis and hypertension, and also serves as a drug delivery platform to provide combinatorial therapeutic options for periodontitis with complicated pathogenesis.